The epidermal growth factor receptor (EGFR) is a tyrosine kinase receptor which plays an integral part in signaling pathways that control normal and malignant cell growth. Although diverse types of EGFR genetic alterations have been detected, the most common acquired genetic alterations of EGFR in human cancers appear to be partial deletions of the extracellular domain. The most common of these truncated receptors is the activating variant III EGFR deletion mutant (EGFRvlll). However, due to the complex structure of the EGFR gene locus, genomic confirmation of EGFRvlll existence in lung and other types of cancer has been difficult. Furthermore, the role of EGFRvlll in the pathogenesis of lung cancer is not known. Our laboratory has recently established the common prevalence of EGFRvlll in human lung squamous cell carcinoma and demonstrated the oncogenic potential of EGFRvlll in the lung through an inducible bitransgenic mouse model. Furthermore, we showed that EGFRvlll transformed cells and tumors are sensitive to irreversible small molecule EGFR inhibitors. Our established model systems offer a unique opportunity to explore the mechanisms by which EGFRvlll mutations deregulate cell growth, to elucidate the genetic interaction between EGFRvlll and the loss of other lung cancer relevant tumor suppressor genes, and to test novel therapeutics for the treatment of EGFRvlll bearing tumors. We hypothesize that lung EGFRvlll bearing tumors with concurrent PTEN, p53 or lnk4a/ARF loss will be more aggressive and be more resistant to EGFR inhibitor treatment. We also hypothesize that chronic EGFR inhibitor treatment of lung tumors or transformed cells bearing EGFRvlll might lead to the development of acquired resistance through the acquisition of new mutations in the EGFR gene. Lastly, we believe that the EGFRvlll is common in other cancer types. Testing of these hypotheses through successful implementation of our specific aims will advance our understanding of the role of the EGFRvlll mutation in tumorigenesis and provide new insights into the development of effective therapeutics for the treatment of different types of cancers that bear EGFRvlll.